ACVR1 – Congenital Heart Disease

Heterozygous variants in ACVR1 have been identified in individuals with congenital heart disease, specifically atrioventricular septal defects (AVSD). Sequencing of 32 AVS-related genes in one cohort revealed two novel missense substitutions, p.Arg307Leu and p.Leu343Pro, each in a single unrelated proband, with the p.Leu343Pro allele showing impaired in vitro kinase function and dominant-negative activity in zebrafish (PMID:19506109). A separate screen in a patient with Down syndrome and AVSD identified p.His286Asp, which exhibited reduced BMP-specific transcriptional response and mild dominant-interfering effects in vivo (PMID:21248739). Together, these findings support a model in which altered ALK2 receptor activity disrupts AV septum formation.

Scores

• Clinical validity: Limited
  • Rationale: 2 probands with no segregation data ([PMID:19506109]; [PMID:21248739])
• Genetic evidence: Limited
  • Rationale: 2 unrelated heterozygous missense variants in [ACVR1] associated with AVSD ([PMID:19506109]; [PMID:21248739])
• Functional evidence: Moderate
  • Rationale: In vitro kinase and BMP transcription assays demonstrated impaired receptor activity of p.Leu343Pro and p.His286Asp; zebrafish models showed dominant-negative effects ([PMID:19506109]; [PMID:21248739])

Key take-home: ACVR1 heterozygous missense alleles may act dominantly to disrupt BMP signaling and contribute to AV septal defects, warranting consideration in genetic testing for congenital heart disease.

References

• Circulation • 2009 • Dominant-negative ALK2 allele associates with congenital heart defects PMID:19506109
• European Journal of Human Genetics • 2011 • ALK2 mutation in a patient with Down's syndrome and a congenital heart defect PMID:21248739

Evidence Based Scoring (AI generated)